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Pathology Review Flash Cards for Revision Neuro, Derm, Bone, Fem Gen. Spring 2009. Neuro - Tissue Reactions. Anoxia Neurons most sensitive to anoxia reside in the hippocampus, Purkinje cells, and larger neocrotical neurons Affect watershed areas first “red” shrunken neurons

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Pathology review flash cards for revision neuro derm bone fem gen l.jpg

Pathology Review Flash Cardsfor RevisionNeuro, Derm, Bone, Fem Gen

Spring 2009


Neuro tissue reactions l.jpg
Neuro - Tissue Reactions

Anoxia

Neurons most sensitive to anoxia reside in the hippocampus, Purkinje cells, and larger neocrotical neurons

Affect watershed areas first

“red” shrunken neurons

Decreased consciousness can result from diffuse axonal injury in absence of localizing findings with trauma

Due to stretching and tearing of axons

Primary reaction to injury – edema

Return of function related to resolution of edema

Liquefactive necrosis


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Bacterial Meningitis

Suppurative involvement of the meninges

Located in subarachnoid space; communicates with CSF

Hematogenous dissemination

No complement in CSF

CSF

Increased protein, decreased glucose

PMNs

Gram stain – bacteria

Positive culture

Clinical features

Headache, fever

Nuchal rigidity, Kernig’s sign

Focal neurological deficits

Increased intracranial pressure


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Other Infections

Viral meningitis

“aseptic meningitis”

Slight increase protein, no decrease in glucose

Lymphocytes

Echovirus, mosquito-borne viruses (west nile virus, eastern equine virus)

Brain Abscess

“ring” enhancement of abscess

central area of low density, & surrounding area of low density due to edema

fibrosis around abscess

CSF – increased protein, few cells



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Syphilis

Meningovasculitis

Infiltration of meninges and vessels by lymphocytes and plasma cells; may cause symptoms of meningitis or vascular occlusion.

General Paresis

Atrophy, loss of cortical neurons especially in frontal lobes, gliosis, proliferation of microglial cells (rod cells), perivascular lymphocytes and plasma cells.

Tabes Dorsalis

Inflammatory lesions involving dorsal nerve roots. Loss of axons and myelin in dorsal roots with Wallerian degeneration of dorsal columns. (T. pallidum is absent in cord parenchyma.)


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Encephalitis

Viruses

Headache, fever, seizure, altered consciousness

Increased intracranial pressures, no other CSF findings

Neonates and immunosuppressed – herpes, cytomegalovirus, HIV

Adults – vector-borne infections (West Nile, eastern equine, etc.); polio

Most hematogenous

Spread along nerves: rabies, herpes simplex

Pathology

perivascular cuffing by lymphocytes and plasma cells;

neuronal necrosis;

inclusion bodies;

microglial proliferation and glial nodules;

hemorrhagic necrosis

rod cells: reactive microglial cells


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Specific Pathologic Findings

Herpes

Necrosis and hemorrhages in temporal lobe

Cytomegalovirus

Owl’s eye nuclear inclusions; cytoplasmic inclusions

Periventricular necrosis, focal calcifications

Rabies

Negri bodies in purkinje cells of cerebellum


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HIV

Immunosuppression

Cryptococcus (india ink preparation) – mononuclear, normal protein, normal glucose

Herpes, cytomegalovirus, toxoplasmosis, PML

AIDS-Dementia Complex

cognitive, motor, and behavioral dysfunction. The symptoms are due to subcortical lesions, with microscopic changes mainly in basal ganglia, thalamus and subcortical white matter

HIV antigen is found in microglia, macrophages and multinucleated giant cells (formed by fusion of macrophages)

Microscopic changes include: foci of necrosis, gliosis, and/or demyelination, microglial nodules, multinucleate cells


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Progressive multifocal leukoencephalopathy

more common in immunosuppressed

intellectual deterioration and dementia over months

JC papovavirus

multiple (multifocal) areas of demyelination in the white matter

little, if any, inflammatory reaction

Inclusion bodies found in oligodendrocyte nuclei, large astrocytes with bizarre nuclei


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Subacute Sclerosing Panencephalitis

rare disease of children and adolescents

associated with a defective measles virus (myxovirus)

personality changes, intellectual decline progressing to dementia. The course is progressive deterioration, with a duration of 1 month to several years.

Changes involve both white matter and gray matter with cortical atrophy and demyelination.

Oligodendrocytes and neurons contain inclusion bodies


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Spongiform Encephalopathy

Creutzfeldt-Jakob Disease

40 and 80 years of age

sporadic; transmission has occurred by corneal transplant or administration of contaminated growth hormone

dementia and myoclonus

deterioration, with death occurring usually in 3-12 months

routine CSF findings are usually normal

spongiform encephalopathy in gray matter throughout brain and spinal cord

Kuru - cannibalism

"Mad Cow" Disease – new variant CJD


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Toxicities

Alcholol

Associated with petechial hemorrhages and gliosis of the mamillary bodies, discoloration of structures (hemosiderosis) surrounding the third ventricle, aqueduct, and fourth ventricle

toxic vs. nutritional; DEFICIENCY OF THIAMINE

peripheral neuropathy

bilateral limb numbness, tingling, and paresthesia

alcoholic cerebellar degeneration; ataxia, wide-based gait; cerebellar vermic atrophy

cognitive problems and dementia

psychiatric: anxiety, hallucinations, paranoid delusions


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Toxicities

Korsakoff’s psychosis– anterograde amnesia and milder retrograde amnesia; impairment in visuo-spatial, abstract, and conceptual reasoning; confabulation; reponds variably to thiamine replacement

Wernicke’s syndrome – sixth nerves palsy and ataxia; nystagmus

clinical triad: ophthalmoplegia, ataxia, and global confusion

disoriented, indifferent, and inattentive; ocular nystagmus on lateral gaze; lateral rectus palsy (usually bilateral); conjugate gaze palsies, and ptosis

ataxia improves more slowly than the ocular motor abnormalities


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Toxicities

Systemic Diseases

Liver failure (alcoholic cirrhosis): hyperammonemia – asterixis

Uremia: symmetric, peripheral neuropathy

Diabetes

Bilateral symmetrical neuropathy

Autonomic instability

Neurogenic bladder

Nutritional

subacute combined degeneration – Vitamin B12

generalized weakness and paresthesias; loss of vibration and position sense; motor defects limited to legs; mental symptoms include irritability, apathy, somnolence, suspiciousness, confusional psychosis, and intellectual deterioration

folic acid deficiency: developmental abnormalities, especially closure of neural tube


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Trauma – Intracranial Hemorrhages

Epidural hematoma

Middle meningeal artery

“lucid” interval between an initial loss of consciousness and later accumulation of blood

Worse prognosis (comatose, herniation)

Subdural hematoma

Delayed onset of symptoms – headache and confusion

Localized hematoma in association with skull fracture

Tearing of bridging veins beneath the dura

Duret hemorrhages

Medial temporal lobe herniation

Example: streptococcal meningitis

Tearing of branches of basilar artery

Hemorrhagic infarcts in the midbrain and pons

Ventral-to-dorsal orientation



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Berry Aneurysm

Congenital weakness of intracerebral artery wall (1 in 100)

Saccular aneurysm near Circle of Willis

If ruptures, results in subarachnoid hemorrhage (headache, blood in CSF)

Rupture when reach 4-7 mm

Often asymptomatic until rupture

Associated with other malformations, familial syndromes

Autosomal dominant polycystic disease

Ehler’s-Danlos syndrome

Does not result in herniation


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Other Hemorrhages

germinal matrix hemorrhage

Premature infants

Hypoxemia, hypercarbia, acidosis, changes in blood pressure

Hemorrhage into germinal matrix

Extend into cerebral ventricles (intraventricular hemorrhage)

Organization of blood can lead to obstruction of aqueduct of Sylvius and hydrocephalus

“coup” injury

Injury to stable head adjacent to site of blow

contrecoup injury

Moving head strikes a stable object

Force is transmitted to opposite side of the head

Backward fall – contusions to inferior frontal lobes, temporal tips, and inferior temporal lobes


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Alzheimer’s Disease

Progressive dementia with memory loss

Neurofibrillary tangles

Hippocampus, amygdala, neocortex

“congophilic angiopathy” – deposition of amyloid in arteriolar media

Multiple associations

Formation and aggregation of the Ab peptide derived from abnormal processing of amyloid precursor protein; cleavage by b-secretase

Inheritance of ApoE4 gene

Mutations in presenilin genes

Cerebral atrophy (hydrocephalus ex vacuo)


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Degenerative Diseases

Parkinson’s

Clinical findings

Difficulty initiating movement

Muscular rigidity

Expressionless facies

“pill-rolling” tremor

Loss of pigmented neurons in substantia nigra

Pick’s disease

Similar to Alzheimer’s, but more frontal features and less memory loss

“knifelike” gyral atrophy of frontal and temporal lobes; sparing of parietal and occupital lobes

Pick bodies – intracytoplasmic, fainty eosinophilic rounded inclusions

Stain for tau protein


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Degenerative Diseases

Huntington’s Chorea

Midlife

Autosomal dominant

Worsening choreiform movements

Behavioral change without memory loss

Expansion of CAG repeats on chromosome 4 (huntingtin gene)

Atrophy, neuronal loss with gliosis in caudate, putamen, and globus pallidus

Dementia with Lewy bodies

Clinical features of Alzheimer’s and idiopathic Parkinson’s

Spheroidal, intraneuronal, cytoplasmic, eosinophilic inclusions – stain for a-synuclein


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Inherited Degenerative – Children

Tay-Sachs

Disease of infancy and childhood

Deficiency of hexosaminidase A

Metachromatic leukodystrophy

Affect white matter extensively

Cause myelin loss and abnormal accumulation of myelin

Lysosomal enzyme defects


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Multiple Sclerosis

Lesions separated in time and space

Central demyelination (oligodendrocytes)

Progressive with relapses and remissions

Optic nerve most common presentation

Oligoclonal immunoglobulins in CSF

Both motor and sensory


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Ischemic Stroke

Involves thrombotic obstruction of arterial flow

Most common: thrombosis of atherosclerotic plaque and downstream ischemia

Less common: embolic disease

Most common: middle cerebral artery

Primary pathophysiology: advanced atherosclerosis, atherosclerosis of carotids, hypercholesterolemia

May be preceded by transient ischemic attacks


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Ischemic Stroke

Involves cortex, aphasia

particularly speech areas

Broca – motor

Wernicke - receptie

Contralateral, differential between upper and lower limbs (homunculus)

Rapidly progressive, may reverse with return of blood flow

Initial injury: edema which reverses

Necrosis leads to liquefactive necrosis, atrophy

Remote cyst formation


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Hemorrhagic stroke

Hemorrhage in area of internal capsule, putamen,

Primary pathophysiology: hypertension

Progression depends on rate and size of bleed

May result in increased intracranial pressures and herniation

Contralateral weakness, sensory loss

Both limbs, distal>proximal

No aphasia (except motor dysarthria)


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Lacunar infarcts

Hypertension of straight penetrating end arteries of middle cerebral artery

Hypertension leads to arteriolosclerosis and narrowing of lumen

Chronic ischemia leads to development of cysts (remember necrosis of brain results in liquefactive necrosis) – lacunae

Area of internal capsule

May precede hemorrhagic stroke

Usually incidental finding


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Arteriovenous malformation

Young to middle aged adults (Senator Tim Johnson)

Mimic tumor, stroke

Mass lesion consisting of tortuous vessels

Frontal lobe – behavior changes, seizures

May bleed slowly or suddenly

Gliosis (reaction to slow blood leakage)


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Neoplasms

Neoplasias of glial cells and epithelial linings, not axons or nerves

Differential

Adult vs. children

Rate of development (years to weeks)

Location (cerebral vs. extracerebral vs. spinal cord)

Morphology on CT (diffuse vs. well demarcated)


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Tumor vs. Other

Length of development – subacute

Localizing signs and symptoms

Unilateral

Specific location – visual, symptoms

Seizure activity

Primary (solitary) vs. Metastases (multiple)

Intracerebral

Tumor emboli settle in vessels in gray-white junction

Don’t metastasis outside of cranium; within cranium, spread through arachnoid space


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Adults

Meningioma

Most common benign brain tumors

30% of adult brain and CNS tumors

Dural (extracerebral) location, growth over months, well-cricumscribed, often asymptomatic until large

Tumor of arachnoid - elongated cells with pale, oblong nuclei, pink cytoplasm, psammoma bodies


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Adults

Glioblastoma multiforme

25% of adult tumors (half of glial tumors)

Most common intracranial malignant tumor

Middle age

Rapidly progressive intracerebral gowth (weeks to months)

Invasive, not circumscribed

Necrosis, nuclear pseudopalisading, hyperchromatic cells

Perinecrotic palisading

Glomeruloid vascular proliferation


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Adults

Astrocytomas

large nuclei, prominent fibers, and negligible mitotic activity

Oligodendromas

Intracerebral glial tumors

Solitary, well-circumscribed masses

Homogeneous cells with dark nuclei, stain with GFAP

Oligodendromas vs. astrocytomas

Astrocytomas less well circumscribed

Astrocytomas more common


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Other Adult

Cerebral lymphoma

HIV patients

B-cell large cell lymphoma (CD19, CD20)

Ependymomas

Arise in ventricles or spinal canal

Rare in adults

Myxopapillary variant – more common in adults than children

Cuboidal cells around papillary cores in a myxoid background

Arise in ventricles

Schwannomas

Cerebellopontine angle, eighth nerve


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Children

Most commonly occur in posterior fossa

Involve cerebellum – ataxia, gait disturbances

Block CSF flow, cause hydrocephalus

Astrocytoma – best prognosis

Pilocytic astrocytoma – cystic cerebellar astrocytoma

Older children

Stain with GFAP, long cellular processes


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Children

Medulloblastoma

Peak age 5 years

Midline, small blue round cells

Homer Wright pseudo-rosettes

Poor prognosis

Ependymoma

Older children and adolescents

Floor of fourth ventricle

Tumor rosettes

Poor prognosis


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Spinal Cord Tumors

Intramedullary (10%)

Ependymomas

Astrocytomas

Glioblastomas

Extramedullary (90%)

Schwannomas

Neurofibromas

Meningiomas


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Neurofibromatosis

Familial syndromes – neurocutaneous syndromes

Type I (peripheral)

Autosomal dominant

Café au lait spots

Schwannomas (cranial nerves, peripheral nerves, neurofibromas (intracranial)); may be multiple

Plexiform neurofibromas

Type II (Central)

Autosomal dominant (chromosome 22)

Bilateral schwannomas of the eighth nerves or multiple meningiomas


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Tuberous Sclerosis

“phakomatoses” – hamartomas and neoplasms develop throughout the body

Cutaneous abnormalities

Cortical tubers – hamartomas of neuronal and glial tissues

Other features

Renal angiomyolipomas, renal cysts

Subungual fibromas

Cardiac rhabdomyomas


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Increased intracranial pressure

Symptoms

Papilledema

Cranial nerve dysfunction (bilateral)

Increased opening pressure on spinal tap (check for papilledema first!)

Progressive evolution of loss of consciousness, herniation

Hydrocephalus

Communicating

Non-communicating

Hydrocephalus ex-vacuo


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Forms of Herniation

Cingulate gyrus herniation

Midline shift

Uncal herniation

Cerebellar tonsil herniation

Downward displacement (central herniation)


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Developmental Defects

Anencephaly

absence of the brain or of all parts except the basal ganglia, brainstem and cerebellum.

failure of closure of the anterior neuropore

Elevated maternal serum a-fetoprotein

Holoprosencephaly

cerebral hemispheres fail to divide properly.

associated with trisomy 13-15 and other chromosomal defects

total or partial lack of division of telencephalic vesicles, optic vesicles, and/or olfactory vesicles


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Developmental Defects

Meningomyelocele

meninges and spinal cord protrude through overlying defect in the vertebral column

lumbosacral location.

also have hydrocephalus and Arnold-Chiari malformation

Encephalocele

meninges and brain tissue protrude through a skull defect.


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Spinal Column

Spina bifida - general term for a midline skeletal defect in the spine of any type.

Spina bifida occulta - closure defect of posterior vertebral arch; may be associated with overlying dimple, hair

Congenital dermal sinus - least serious and most common mid-line defect. Defects range from dimpling of skin over lumbosacral area to sinus tracts in this region.

Meningocele - sac containing meninges & CSF protrudes through skeletal defect (rare)

Syringomyelia – cervical vertebrae


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Dandy-Walker

malformation of vermis (anterior vermis displaced rostrally, inferior vermis reduced to abnormal white matter on medial surfaces of hemispheres)

cystic dilatation of fourth ventricle, with wall of cyst composed of ependyma and leptomeninges

lateral displacement of cerebellar hemispheres by 4th ventricle

increased volume of posterior fossa, with upward displacement of lateral venous sinuses.

obstruction of foramina of Luschka and Magendie, with production of hydrocephalus


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Arnold-Chiari

Type I (adult type) has variable herniation of cerebellar tonsils and is frequently accompanied by syringomelia

Type II (infantile type), called the Arnold-Chiari malformation here,

polymicrogyria

meningomyelocele

hydrocephalus

beak-shaped colliculi, displacement of the medulla and fourth ventricle down into the cervical segments


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Other

Central pontine myelinolysis

Too rapid correction or normalization of hyponatremia

Osmotic demyelination

Results from chronic adaptation to hyponatremia with formation of intracellular osmoles

Most often a result of alcoholism

Can also occur with rapid normalization of sodium from SIADH

Prognosis is poor


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Response to Injury - Axons

  • segmental demyelination

    • dysfunction of Schwann cellor damage to myelin sheath (no 1° abnormality of axon)

    • disintegrating myelin engulfed by Schwann cells, later macrophages

    • denuded axon undergoes remyelination

      • newly formed internodes are shorter than normal

        • several new internodes are required to bridge gap

      • new myelin thinner than original

      • sequential episodes of demyelination and remyelination leads to concentric skeins and formation of “onion bulbs”


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Response to Injury - Axons

  • axonal degeneration

    • implies primary destruction of axonwith secondary disintegration of myelin sheath

    • may be due to trauma, ischemia, underlying abnormality of neuron or axon

    • response to transection: Wallerian degeneration

      • axon breaks down within one day

      • Schwann cells catabolize myelin and engulf axon fragments

      • macrophage phagocytosis of axonal and myelin debris

      • stump (proximal portion) shows degenerative changes in most distal 2 or three internodes

      • if neuron remains viable, undergoes regenerative activity


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Response to Injury - Axons

  • symptoms associated with neuronal degeneration

    • lower motor neurons - muscular atrophy, fasciculations, weakness

    • upper motor neurons - hyperreflexia, spasticity, and a Babinski reflex

  • nerve regeneration

    • involves growth cone at end of remaining stump

    • multiple, closely aggregated thinly myelinated small-caliber axons (regenerating cluster)

    • haphazard growth and mass of tangled fibers - pseudoneuroma

    • slow rate of axonal transport - growth only 2 mm/day

    • denervated muscle usually re-innervated by adjacent fibers before original fiber regenerates


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Amyotropic Lateral Sclerosis (Lou Gehrig’s Disease)

  • Clinical Characteristics

    • Middle-aged

    • 10% familial; genetic locus Cu/Zn binding superoxide dismutase gene

    • Loss of upper and lower motor neurons

    • Progressive, symmetric muscular weakness

      • May present with bulbar symptoms, with sparing of the extra-ocular muscles

    • Intact mental function; death from respiratory complications

  • Pathology

    • Gliosis and loss of motor neurons

    • Pallor of lateral coricospinal tracts

    • Neuronal loss in anterior horns of spinal cord

    • Denervation atrophy of muscle fibers


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Werdnig-Hoffman disease (infantile progressive spinal muscular atrophy)

  • “floppy infant syndrome”: severe form of lower motor neuron disease which presents in neonatal period

  • death within a few months from respiratory failure or aspiration pneumonia

  • autosomal recessive condition, pathogenesis unknown

  • Morphology

    • severe loss of lower motor neurons with profound neurogenic atrophy of muscle

    • degeneration of motor axons of the anterior roots


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Guillain-Barre Syndrome muscular atrophy)

  • Clinical Characteristics

    • life-threatening diseases of peripheral nervous system

    • death (2-5%) from respiratory paralysis; recovery over several weeks if respiratory function maintained

    • acute illness, symmetric, ascending paralysis(distal to proximal)

    • motor>sensory with loss of deep tendon reflexes

    • elevation of CSF protein (no while cells)

  • Pathology

    • 2/3 cases preceded by influenza-like illness

    • most intense inflammation in spinal and cranial motor roots (anterior roots)

    • autoimmune segmental demyelination; nerve conduction slowed

    • thought to be T-cell mediated, but treatable with plasmapheresis


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Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

  • Clinical Characteristics

    • radiculopathy

    • chronic relapsing, remitting course

    • symmetric, mixed sensorimotor polyneuropathy

  • Morphology - Similar to GB, because of chronic nature, well-developed onion-bulb structures are seen

  • Biopsy of sural nerves shows recurrent demyelination and remyelination with onion bulb structures

  • Clinical remissions with steroid treatment and plasmapheresis


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Infectious Neuropathies (CIDP)

  • Varicella-Zoster (post Chicken Pox)/Shingles

    • latent infection of the sensory ganglia of the spinal cord and brain stem

    • virus transported along sensory nerves to infect epidermal cells; reactivation vesicles appear distributed along dermatome (very painful!!!)

    • reactivation may be related to decreased cell mediated immunity

    • affected ganglia show neuronal destruction with abundant mononuclear infiltrates; regional necrosis with hemorrhage


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Hereditary Neuropathies (CIDP)

  • HMSN I (Charcot-Marie-Tooth disease)

    • autosomal dominant/most common

    • presents in childhood or early adulthood; normal life span; limited disability

    • progressive, symmetric muscular atrophy, particularly in the calf muscles (peroneal muscular atrophy)

    • suggests Schwann cell abnormality

      • palpable nerve enlargement/hypertrophy - demyelination and remyelination of peroneal nerve

  • HMSN II - similar to HMSN I, presents at later age and nerve enlargement is not seen; autosomal dominant

  • HMSN III (Dejerine-Sottas disease)

    • AR; present in infancy; delay in acquisition of motor skills

    • slow progression of distal weakness plus truncal weakness

    • enlarged, palpable peripheral nerves, onion bulb formation


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Acquired Metabolic and Toxic Neuropathies (CIDP)

  • Hand/foot (distal) symmetric distribution

  • Numbness tingling (primarily sensory)

  • diabetes mellitus, alcoholism, uremic neuropathy

  • industrial or environmental chemicals - axonal degeneration

    • acrylamide, heavy metals (arsenic, lead), vinca alkyloids (plants, drugs), organophosphates (pesticides)

  • tumor-associated syndromes


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Tumor-associated syndromes (CIDP)

  • direct infiltration or compression of peripheral nerves (Pancoast’s; cauda equina involvement)

  • Plasma cell dyscrasias(Two types)

    • Amyloid (light chain depostion) vs. monoclonal IgM gammopathy

    • compression syndromes - similar to carpal tunnel syndrome

  • Paraneoplastic syndromes - solid tumors

    • most often associated with small cell carcinoma of the lung

    • degeneration of dorsal root ganglion cells with proliferative responses by satellite cells and inflammatory infiltrates

      • plasma cells and lymphocytes, predominantly CD8

    • sensorimotor lesion - weakness and sensory deficits more pronounced in the lower extremities that progress over months to years

    • Eaton-Lambert syndrome


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Schwannomas (CIDP)

  • Benign

    • neural crest derived Schwann cells

    • within cranial vault, most common location is the cerebellopontine angle, attached to eighth nerve

    • extradural tumors most commonly found in association with large nerve trunks

  • Malignant schwannoma (malignant peripheral nerve sheath tumor, MPNST)

    • highly malignant, locally invasive

    • multiple recurrences with eventual metastatic spread

    • never arise from malignant degeneration of benign schwannoma; arise from plexiform neurofibromas (NF-1)


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Neurofibroma (CIDP)

  • Cutaneous/peripheral nerve form

    • markers of diverse lineages, including Schwann cells, perineurial cells, and fibroblasts

    • Unencapsulated, highly collagenized masses of spindle cells

  • Plexiform neurofibroma

    • defining lesion of neurofibromatosis type 1

    • difficult to remove surgically

    • high potential for malignant transformation; frequently multiple


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Myasthenia gravis (CIDP)

  • Clinical features

    • if before age 40, F>M

    • motor weakness which fluctuates – increases with muscle use

      • exacerbations by intercurrent illness

      • sensory and autonomic functions not affected

    • characteristic temporal and anatomical distribution

      • extraocular muscles commonly involved (ptosis and diplopia)

  • Diagnostic features

    • decrement in motor responses with repeated stimulation

    • Tensilon test: transient improvement when administered anticholinesterase agents


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Myasthenia gravis (CIDP)

  • decrease in number of muscle acetylcholine receptors secondary to anti-receptor antibodies

    • can be passively transferred to animals

    • circulating anti-AChR causes decrease in receptor number (increased receptor internalization and destruction) and damage to post-synaptic membrane secondary to complement fixation

  • often associated with thymic hyperplasia or thymomas; patients respond to thymectomy

  • Morphology

    • muscle biopsies unrevealing; may have diffuse changes with Type 2 atrophy

    • immune complexes present in synaptic cleft

    • thymic hyperplasia with germinal centers


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Eaton-Lambert syndrome (CIDP)

  • paraneoplastic syndrome (most commonly small cell carcinoma of the lung)

  • proximal muscle weakness with autonomic dysfunction

  • does not respond to Tensilon test or show increased weakness with repetitive stimulation

  • ACh receptors OK, but fewer vesicles are released on synaptic transmission

  • passive transfer of syndrome with IgG


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Botulism (Clostridium botulinum) (CIDP)

  • secondary to toxin production in improperly prepared foods or an anaerobic infection

    • No infection with organism; absoption of ingested toxin

    • Neonates: necrotizing intestinal infection by C. botulinum from honey

  • paralysis due to disruption of presynaptic neurotransmitter release


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Types of muscle fibers (CIDP)

  • Determinant of muscle fiber type - determined by the motor neuron that innervates it (i.e., if the neuron type changes, the muscle type will change along with it); staining for ATPase


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Response to Injury - Muscle (CIDP)

  • Denervation atrophy - secondary to axonal loss

    • group atrophy - type group becomes denervated

    • down regulation of myosin and actin synthesis

    • decreased cell size with resorption of myofibrils

    • cytoskeletal reorganization - rounded zone of disorganized fibers (target fiber)

    • type 2 fiber atrophy - inactivity or disuse; also pyramidal tract disorders, neurodegenerative diseases

  • Reinnervation

    • muscle fibers re-innervated by sprouts from adjacent nerves incorporated into muscle fiber group for that nerve

    • orphaned fibers assumes fiber type of neighbors; leads to type grouping


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Response to Injury - Muscle (CIDP)

  • Primary damage to muscle - segmental necrosis

    • primary reaction of muscle fiber

    • results in myophagocytosis

  • Regeneration

    • cells recruited from satellite population

    • regenerating cells large, with internalized nuclei; basophilic due to increased RNA content

    • vacuolation; intracytoplasmic deposits with loss of fibers; deposits of collagen, fatty infiltration

  • Hypertrophy - secondary to increased load

  • Muscle fiber splitting - invagination of membrane along large fibers, with apparent splitting of fiber


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Duchenne’s muscular dystrophy (CIDP)

  • Epidemiology

    • X-LINKED (1/3500 males)

    • female carriers show increased plasma levels of creatine kinase and mild muscle damage

    • mutations in gene for dystrophin; 1/3 new mutations

  • Clinical Characteristics

    • most severe of the dystrophies

    • early motor milestones met on time; develop inability to keep up with peers

    • clinically manifest by age of five; wheelchair by 10 or 12

    • weakness begins in pelvic girdle muscles and extends to shoulder; use of arms to get up called “Gower’s maneuver”

    • cognitive impairment to mental retardation


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Duchenne’s muscular dystrophy (CIDP)

  • Morphology

    • degeneration, necrosis, and phagocytosis of muscle fibers

    • variation in muscle fiber size with both small and giant fibers; fiber splitting

    • increased numbers of internalized nuclei (muscle regeneration)

    • replacement of muscle fibers by fatty infiltrate

  • Clinical Findings

    • serum creatine kinaseelevated in first decade; may return to normal as muscle is destroyed

    • enlargement of calf muscles: pseudohypertrophy

    • progressive; death by early 20’s from respiratory insufficiency, lung infection, or cardiac decompensation

      • changes in heart result in heart failure or arrhythmias


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Becker’s Muscular Dystrophy (CIDP)

  • X-LINKED RECESSIVE

  • similar to Duchenne’s, but less common and less severe

  • onset later in childhood and into adolescence

  • slower, variable rate of progression

  • involves changes to, not loss of dystrophin gene locus

  • normal life span with rare cardiac involvement


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Other (CIDP)

  • Facioscapulohumeral muscular dystrophy

    • AUTOSOMAL DOMINANT

    • disease of adolescents-young adults

    • weakness of muscles of face, neck, and shoulder girdle

    • dystrophic myopathy with inflammatory infiltrate

  • Limb-girdle dystrophy

    • AUTOSOMAL RECESSIVE/SPORADIC CASES

    • onset as adolescent or young adults

    • weakness of proximal muscles of upper and lower extremities

    • progression variable; variable dystrophic myopathy


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Myotonic dystrophy (CIDP)

  • Myotonia = sustained involuntary contractions

    • patients c/o stiffness, unable to release grip

    • percussion of thenar eminence elicits myotonia

  • Epidemiology/inheritance

    • AUTOSOMAL DOMINANT

    • increasingly severe and at younger age in succeeding generations: ANTICIPATION

  • Etiology/Pathogenesis

    • gene for myotonin-protein kinase, unstable mutation

    • damage collects with each generation


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Myotonic dystrophy (CIDP)

  • Clinical Characteristics

    • late childhood with gait difficulties, foot weakness

    • progresses to involve hand and wrist extensors

    • atrophy of muscles of face (ptosis)

    • cataracts present in nearly every patient

    • also: frontal balding, gonadal atrophy, cardiomyopathy, smooth muscle involvement, decreased plasma IgG, and abnormal glucose tolerance test

  • Morphology

    • muscle dystrophy similar to DMD

    • increase in the number of internal nuclei in chains

    • ring fibers

    • relative atrophy of Type I fibers

    • dystrophic changes in muscle spindle fibers (unique)


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Congenital Myopathies (CIDP)

  • onset in early life, nonprogressive or slowly progressive course, proximal or generalized muscle weakness, hypotonia; “floppy babies” or may have severe joint contractures

  • Syndromes

    • Nemaline myopathy

    • Lipid myopathies

    • Mitochondrial myopathies

    • Cradle’s syndrome

    • Pompe’s disease

  • Also: ion channel myopathies (periodic paralysis and myotonia associated with hyper-, hypo-, or normokalemia

    • malignant hyperthermia – dramatic hypermetabolic state associated with induction of anesthesia; familial susceptibility


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Toxic Myopathies (CIDP)

  • thyrotoxic myopathy - proximal muscle weakness, fiber necrosis with regeneration, interstitial lymphocytes; focal myofibril degeneration with fatty infiltrate

  • hypothyroidism - cramping and aching of muscles with slowed reflexes and movements; fiber atrophy, internal nuclei, glycogen aggregation, accumulation of mucopolysaccharides (myxedema)

  • thyrotoxic periodic paralysis- episodic weakness often accompanied by hypokalemia; M>F, Japanese descent; dilatation of sarcoplasmic reticulum and intermyofibril vacuoles

  • alcohol-induced - drinking with RHABDOMYOLYSIS/ myoglobinuria; pain generalized or confined to single muscle group; swelling of myocytes with fiber necrosis, myophagocytosis, and regeneration


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Loss of Pigment (CIDP)

  • Vitiligo

    • Irregular, well-demarcated macules devoid of pigment

    • Loss of melanocytes

      • autoimmunity

      • neurohumoral factors

      • toxic melanin synthesis metabolites

  • Albinism

    • Congenital absence of pigmentation

      • Multiple abnormalities


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Increased Pigmentation (CIDP)

  • Freckles (ephilis)

    • Tan-red to brown macules

    • ↑ with sun exposure

    • Normal number of melanocytes

    • ↑ melanin within basal keratinocytes

  • Melasma

    • Darkening of skin

    • Under hormonal control (menopause, pregnancy)

  • Lentigo

    • Macular (flat), delimited pigmented area


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Nevi (CIDP)

  • Progression

    • begins as small tan dot; grows as uniformly colored tan-brown area with well-defined, rounded borders

    • after 1-2 decades gradually flattens and returns to normal

  • Maturation of Nevi

    • migration of cells into dermis accompanied by process termed “maturation”

    • less mature, more superficial cells are larger, produce more melanin pigment, grow in nests

    • more mature, deeper nevi cells are smaller, produce little or no pigment, grow in cords

    • the lack of maturation in melanomas is a key feature distinguishing melanomas from nevi


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Nevi (CIDP)

  • Junctional/Compound/and Dermal forms

    • Cells migrate to dermis on maturation

  • change from dendritic single cells to nests of round to oval cells

  • increase in number of melanocytes in basal epidermal layer with hyperpigmentation

  • form nests at tips of rete ridges

  • migrate into dermis to form cellular lesion

  • dermal components differentiate along lines of Schwann cells

  • core of 20 yr. old nevus composed of neuromesenchyme

  • undergoes fibrosis, flattening, eventual disappearance


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Dysplastic Nevi (BK moles) (CIDP)

  • Pathogenesis

    • autosomal dominant, familial syndromes associated with hundreds of lesions on body surfaces (both sun exposed and non-exposed areas)

    • may be associated with chromosomal instability

    • most are clinically stable, but may undergo stepwise progression to malignant melanoma

  • Pathology

    • larger than usual nevi; flat macules with variegation of pigmentation

    • characterized by abnormal pattern of growth and aberrant differentiation; cytologic atypia

    • focal areas of eccentric melanocytic growth

    • associated with subjacent lymphocytic infiltrate


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Melanoma (CIDP)

  • Color or size change of pre-existing mole or new lesions

  • Asymmetrical, irregular borders, variegated colors

  • Large, irregular nuclei w/clumped chromatin and red nucleoli

  • Radial growth first, then vertical growth

    • Degree of vertical growth is predictive of prognosis

  • Lymphocytic infiltrate

    • Immune reaction important in controlling progression of tumor

  • Assoc. w/p16INK4a


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Seborrheic keratosis (CIDP)

  • Clinical features

    • middle aged or older individuals; commonly affect trunk

    • multiple small lesions on face of blacks: dermatosis papulosa nigra

    • sign of Leser-Trelat: paraneoplastic syndrome

  • Pathologic features

    • well-demarcated, flat, coin like plaques mm-cm

    • uniformly tan to dark brown

    • velvety to granular surface

    • trabecular arrangement of sheets of basilar cells with keratin pearls

    • pores impacted with keratin with keratin-filled cysts

    • variable melanin pigmentation in basilar cells***


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Acanthosis Nigricans (CIDP)

  • Clinical features

    • cutaneous marker for associated benign and malignant conditions

      • benign: 80% heritable trait/obesity/endocrine disease/rare congenital syndromes

      • malignant type: underlying adenocarcinoma

    • hyperpigmented zones of skin involving flexoral areas – axilla, skin folds of neck, groin, and anogenital areas

  • Pathogenesis

    • may be associate with abnormal production of epidermal growth factors


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Keratoacanthoma (CIDP)

  • Clinical features

    • rapidly developing benign neoplasm; 1-several cm.

    • resembles squamous cell carcinoma but may heal spontaneously

    • flesh-colored, dome-shaped nodules with central, keratin-filled plug

  • Pathologic features

    • keratin-filled crater surrounded by lip of proliferating epithelial cells

    • atypical, eosinophilic. "glassy" cytoplasm; stromal response with inflammatory cells

    • host response may determine regression or progression



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Skin Cancer (CIDP)

  • Squamous cell carcinoma

    • Sharply defined, red scaly lesions

    • Sheets w/keratin pearls and intracellular bridging

    • Can involve oral mucosa

    • Assoc w/p53, immunosuppression, HPV, UVB, dysfxn of Langerhans cells

  • Basal cell carcinoma

    • Pearly papules, telangiectasia

    • Local destruction and invasion of bone and sinuses

    • Palisading cells in tumor nests and tongues

    • Lymphocytic infiltrate

    • Familial: two hit hypothesis

    • Sporadic: PTCH, p53



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Urticaria and Angiodema (CIDP)

  • hives: raised, pale, well-delimited pruritic areas; appear/ disappear within hours

    • represent edema of the superficial portions of the dermis

  • angioedema: egglike swelling with prominent involvement of deeper dermis and subcutaneous fat

  • Worse in areas of rubbing and warmth, skin folds due to increased vascular flow (waistband, neckline, under breasts, etc.)

  • Vascular reaction mediated by vasoactive substances

    • degranulation of mast cells: IgE-mediated allergic responses or complement-mediated responses

    • direct release of histamine by physical stimuli (cold)

    • non-specific release of mediators by mast cells by drugs or neurological response


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Acute Eczematous Dermatitis (CIDP)

  • Type IV cell-mediated hypersensitivity; prototype: poison ivy

  • immunologically specific, mononuclear, inflammatory response that reaches its peak 24 to 48 hour after antigenic challenge

  • intensely pruritic, fiery red, with numerous vesicles

    • “eczema” means to boil-over – redness, oozing plaques, vesicle formation

  • requires previous sensitization: develops 7-10 days after 1st challenge; 2-3 days on subsequent challenge

  • evolution of lesions from acute inflammation to chronic hypereplastic lesions

    • initial edematous inflammation

    • epidermal spongiosis and microvesicular formation

    • chronic: hyperplasia and hyperkeratosis (acanthosis)

    • prone to bacterial superinfection


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Erythema multiforme (CIDP)

  • self-limited hypersensitivity to certain infections and drugs

  • multiform lesions: macules, papules, vesicles, or bullae

  • associated infections, drug hypersensitivities, tumors, collagen vascular diseases.

    • penicillin, sulfonamides, barbiturates, salicylates, hydantoins, antimalarials

    • lupus, dermatomyositis, periarteritis nodosa

  • bilateral involvement of extremities (especially shins)

  • lymphocyte-mediated epidermal necrosis

    • accumulation of lymphocytes at dermal-epidermal border with dermal edema

    • epidermal necrosis, blister formation; sloughing with shallow erosions

  • variants

    • febrile disease in children: Stevens-Johnson Syndrome

    • toxic epidermal necrolysis


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Pemphigus vulgaris (CIDP)

  • separation of stratum spinosum from basal layer

  • vesicle contains lymphocytes, macrophages, eosinophils, neutrophils and rounded keratinocytes ("acantholytic cells")

  • IgG autoantibodies to intercellular substance of the epidermis (desmoglein)

  • may be associated with other autoimmune diseases such as myasthenia gravis, SLE


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Bullous pemphigoid (CIDP)

  • subepidermal, large tense blisters with erythematous base

  • subepidermal, non-acantholytic blisters

  • roof of vesicle is lamina densa

  • eosinophils predominate cell along with fibrin, lymphocytes, neutrophils

  • mast cell migration from venule toward epidermis

  • autoimmune disease characterized by circulating IgG antibodies to glycoprotein of lamina lucida

  • linear deposition of complement, recruitment of neutrophils, and release of major basic protein


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Epidermolysis bullosa (CIDP)

  • hereditary

  • formation of blisters at sites of minor trauma

  • subepidermal vesicle with few inflammatory cells in dermis

  • Classification

    • epidermolytic epidermolysis bullosa:

      • within basal keratinocytic layer, with intact epidermis

    • junctional epidermolysis bullosa:

      • within lamina lucida

    • dermolytic epidermolysis bullosa:

      • roof of vesicle is lamina densa

  • involve extensive flaws in the dermal component of the basement membrane zone and structural proteins of anchoring filaments, lamina densa


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Psoriasis (CIDP)

  • common, familial (1-2% of population in US)

  • large, erythematous, scaly plaques with silvery scales

    • commonly observed on extensor-dorsal surfaces, Nail changes occur in 30%

  • severe disease may be associated with arthritis, myopathy, enteropathy, etc.

  • Pathogenesis (T-cell mediated):

    • Deregulation of epidermal proliferation& an abnormality in the dermal microcirculation

    • increased TNF associated with lesions; TNF-antagonists provide significant improvements


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Psoriasis (CIDP)

  • Pathology (Entire skin is abnormal)

    • Thickened epidermsis (hyperkeratosis and parakeratosis) w/ a thinned/absent stratum corneum. Dilated and Tortuous Capillaries

    • Elonagated papilla with Munro’s abscesses

      • collections of neutrophils at top of elongated papillae

    • collections of acute inflammatory cells in epidermal spinous layer & mononuclear inflammatory cells in dermis

    • Auspitz' sign – multiple, minute bleeding points when a scale is removed


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Lichen Planus (CIDP)

  • Multiple, symmetrically distributed “pruritic, purple, polygonal papules”

    • usually appear on the flexor surface of the wrists

    • Resolve in 1-2 years

  • Pathologic features

    • prominent band like lymphocytic infiltrate along dermoepidermal junction which replaces papillary/rete ridge

    • degeneration of basal keratinocytes; Saw-toothing of dermal interface

    • fibrillary, eosinophilic bodies represent dead keratinocytes: colloid, Civatte, or Sabouraud bodies

    • hypergranulosis and hyperkeratosis

      • Wickham striae = white dots or lines

  • Pathogenesis = likely T-cell mediated immune reaction to antigens in basal layer


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Dermatitis herpetiformis (CIDP)

  • urticaria-like plaques with eroded erythematous blisters

    • Occur on the elbows, knees, buttocks: Intensely Pruritic

  • adult males (3rd-4th decade)

  • related to HLA-B8/DRW3 haplotype and gluten sensitivity

  •  Pathologic features

    • deposits of granular IgA to gliadan at dermal-epidermal interface, mainly at the tips of the dermal papillae

      • receptor for gluten found in dermal papillae

    • collection of neutrophils at tips of papillae (microabscesses)


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Osteogenesis Imperfecta (CIDP)

  • “Brittle bone disease”

  • Autosomal dominant

  • Deficiencies in type I collagen

  • Affects bones, joints, eyes, ears, skin, and teeth

  • Extreme skeletal fragility, confused with child abuse

  • Major subtypes

    • type I is most common; autosomal domimant; increased fractures, blue sclerae, hearing loss

  • basic abnormality is “too little bone”; marked cortical thinning and attenuation of trabeculae


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Ostopetrosis (CIDP)

  • “Stone bones” or “Marble bone” disease – too much bone formation (too little resorption)

    • bones lack medullary canal, decreased bone marrow

  • Pathologic fractures, anemia, hydrocephaly, cranial nerve dysfunction

    • neural foramina small; cranial nerves compressed

    • abnormally brittle bones; short stature

  • deficient osteoclast activity

    • diffuse symmetric skeletal sclerosis

  • two forms - "malignant" (autosomal recessive; die shortly after birth); "benign" (autosomal dominant; live to adulthood)


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Dwarfism (CIDP)

  • Achondroplastic Dwarfism

    • Autosomal dominant; 80% of cases new mutations

    • Most common disease of the growth plate

    • defect in proliferation of chondrocytes

      • mutation in FGF receptor; inhibition of cartilage formation

    • Normal trunk length, shortened limbs, enlarged head

      • Prominent forehead – “frontal bossing”

    • NO changes in longevity, intelligence, or reproductive status

    • Premature closure of growth plate; Normal growth hormone levels

  • Thanatophoric dwarfism/dysplasia

    • most common form of lethal dwarfism

    • mutation in FGF receptor

    • respiratory insufficiency due to underdeveloped thoracic cavity


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Paget’s Disease (CIDP)

  • Osteitis Deformans - “matrix metabolic madness”

  • Presentation

    • Elderly male

    • Bone pain, axial skeleton – pelvis/skull/femur

    • Cranial nerve compression of nerves, thickened skull (↑’d hat size)

  • Mechanism (?pararmyxovirus)

    • Early phase – inflammatory, Increased osteoclastic resorption with disordered osteoid synthesis

    • Late phase – burned out sclerosis

  • most serious consequence→ development of osteosarcoma (1 - 10%) - jaw, pelvis, or femur

  • Increased alkaline phosphatase, Tile-like mosaic of osteoid formation pathognomonic

  • Urinary excretion of hydroxyproline


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Osteomyelitis (CIDP)

  • Clinical course

    • fever, systemic illness

    • 60% positive blood cultures, radionuclide scans may be helpful if X-rays negative

  • Associations

    • Developed countries, dental/sinus infection → bone

    • Compound fractures

    • Toes and feet of diabetics with chronic ulcers; bone surgery

    • Intravenous drug use

    • Underdeveloped countries, hematogenous spread

    • Ends of long bones most common (esp. children); also vertebrae in adults

  • Pathogenesis

    • 80-90% (penicillin-resistant) ***Staph. aureus***,

    • complication of sickle cell – Salmonella

    • drug addicts – Pseudomonas

      • Also puncture through rubber footwear

    • infants/neonates – Group B streptococcus

    • TB – vetebrae (Pott’s disease and Psoas abscess)


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Osteomyelitis (CIDP)

  • Pathogenesis

    • 80-90% (penicillin-resistant) ***Staph. aureus***,

    • complication of sickle cell – Salmonella

    • drug addicts – Pseudomonas

    • infants/neonates – Group B streptococcus

    • TB – vetebrae (Pott’s disease and Psoas abscess)

  • Morphology

    • sub-periosteal chronic nidus of infection = Brodie's abscess

    • smoldering infection → osteoblastic activity → Garre's sclerosing osteomyelitis

    • devitalized bone (sequestra) surrounded by reactive bone formation (invulcrum)

    • draining sinus tracts to surface

      • Squamous cell carcinoma at orifice of sinus tract


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Fibrous dysplasia (CIDP)

  • benign disorder; risk of pathologic fracture

    • localized bone defects found incidentally

  • replacement of bone and marrow with abnormal proliferation of haphazardly arranged woven bone

  • monostatic (single site) – 70%

    • 70% childhood, arrests at puberty

    • involves ribs, femur, tibia

  • polystatic form (multi-site) – 25%

    • begins earlier, may extend into middle age

    • craniofacial in 50%

    • polystatic with endocrinopathy: 3-5%, skin pigmentation (café au lait spots), precocious sexual development = Albright's


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Aseptic Necrosis (CIDP)

  • Causes

    • mechanical vascular disruption; thrombosis and embolism; vessel injury

    • corticosteroids; radiation therapy; sickle cell anemia; alcohol abuse

  • Morphology

    • cancellous bone, marrow most affected; cortex not affected

    • subchondral wedge-shaped infarcts extending into epiphysis

    • empty lacunae (death of osteocytes)

    • increased bone density (sclerosis)

  • Bone pain

  • Pieces of dead bone that becomes separated is called a sequestrum


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Other (CIDP)

  • Aneurysmal bone cyst

    • Solitary, expansile, erosive lesion of bone

    • Adolescent females (2:1)

    • Metaphysis of lower extremity long bones

    • Secondary to localized hemorrhage due to trauma, vascular disturbance, or increased venous pressure

      • Sometimes secondary to tumors or fibrous dysplasia

    • Tenderness and pain with limited range of motion

    • Appears as cyst on x-ray

www.bonetumor.org


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Osteoporosis (CIDP)

  • Reduced bone mass with increased porosity & thinning of trabeculae & cortex

  • Involves entire skeleton, but some areas more affected than others

  • Increased risk of fractures: femoral neck, vertebral compression fractures, Colles fracture of wrist

  • Not detected by x-ray until 30-40% loss; serum calcium, phosphorus, alkaline phosphatase normal

  • Rx: estrogen replacement therapy, bisphosphanates, PTH, adequate Vit D & calcium, exercise


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Osteoporosis (CIDP)

  • Primary:

    • senile: normal age-related, steady decline in bone mass after 4th decade

      • reduced replicative potential of osteoblasts relative to osteoclastic break-down

      • loss accentuated by reduced physical activity with age

      • women/whites more severely affected due to lower peak bone mass

    • post-menopausal: decreased estrogen→ increased osteoclast activation and bone degradation

  • Secondary: hyperparathyroidism, hypogonadism, pituitary tumors, corticosteroids, multiple myeloma


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Primary Bone Tumors -- benign (CIDP)

  • Osteoid Osteoma

    • Interlacing trabeculae of woven bone surrounded by osteoblasts

    • <2 cm in proximal tibia and femur, pain controlled by NSAIDs

  • Osteoblastoma

    • Same morphology as osteoid osteoma but found in vertebrae

  • Giant cell tumor (20-40)

    • epiphysis of long bones

    • Locally aggressive (necrosis, hemorrhage, reactive bone formation), soap bubble appearance on XR, spindle shaped cells with giant cells (fused osteoclasts)


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Primary Bone Tumors -- benign (CIDP)

  • Osteochondroma (exostosis)

    • Mature bone with cartilagenous cap

    • Men < 25 on metaphysis of distal femur or proximal tibia

  • Enchondroma

    • Cartilagenous, found on distal extremities (compare with chondrosarcoma)

    • Multiple lesions in familial syndromes (Ollier’s syndrome) – predisposes to osteosarcoma and chondrosarcoma


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Primary Bone Tumors -- malignant (CIDP)

  • Osteosarcoma (men 10-20)

    • metaphysis of long bones

    • Associated with Paget’s of bone, LiFraumeni, bone infarcts, radiation, retinoblastoma, mutilpleenchondromas

    • Codman’s triangle = elevated periosteum

  • Ewing’s Sarcoma (boys <15)

    • anaplastic small blue cells (look like lymphocytes: lymphoma, rhabdomyosarcoma, neuroblastoma, oat cell carcinoma)

    • “Onion-skin” of bone and Homer-Wright Rosettes, diaphysis, t(11:22)

    • Medullary cavity; anemia, systemic symptoms (fever)

  • Chondrosarcoma (Men 30-60)

    • can arise from osteochondroma

    • axial skeleton


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Palmar, Plantar, Penile Fibromatoses (CIDP)

  • between reactive proliferation and neoplastic growth

  • Dupuytren's contracture (palmar)

    • irregular or nodular subcutaneous thickening of the palmar fascia with fibrosis, deposition of collagen

    • either unilaterally or bilaterally (50%)

    • slowly progressive flexion contracture, mainly of fourth and fifth fingers

  • plantar involvement occurs without flexion contracture

  • penile fibromatosis (Peyronie's disease) occurs as a palpable induration or mass on the dorsolateral aspect of the penis

  • may be genetic; males>females; 20-25% may stabilize; others may resolve or recur following resection


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Desmoid – Aggressive Fibromatosis (CIDP)

  • extra-abdominal: musculature of the shoulder, chest wall, back and thigh

  • abdominal desmoids

    • Women

    • musculoaponeurotic structures of the anterior abdominal

    • during or following pregnancy

  • intra-abdominal desmoids: mesentery or pelvic walls, often in patients having Gardner's syndrome

  • ?reaction to injury, ?genetic factors; may recur if incompletely excised

  • unicentric, unencapsulated, infiltrate surrounding structures

  • may recur after excision


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Other Non-Neoplastic Conditions (CIDP)

  • Nodular (Pseudosarcomatous) Fasciitis

    • Reactive fibroblastic proliferation –may occur after trauma

    • several week history of a solitary, rapidly growing, painful mass in extremities

    • young and middle-aged adults of either sex

    • attachment to fascia with apparent invasive characteristics

  • Traumatic Myositis Ossificans

    • characterized by presence of metaplastic bone; not restricted to skeletal muscle; not inflammatory; not always ossified

    • preceded by trauma; most often extremities in young, athletically active males

    • cured with excision


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Lipoma/Liposarcoma (CIDP)

  • Lipomas

    • lipomas are the most frequent soft tissue tumor

    • peak incidence 5th and 6th decades

    • arise in subcutaneous tissues, 5% multiple, usually small with delicate capsule

  • Liposarcomas - uncommon

    • arise from primitive mesenchymal cells; no assoc. with adipose tissue

    • retroperitoneum and deep tissues of the thigh (less frequently in the mediastimum, omentum, breast, and axilla)

    • peak in 5th to 7th decades

    • Large, multilobulated with projections into surrounding tissues; cystic softening, hemorrhage, and necrosis are common

    • large, bulky tumors of deep tissues or cavities often recur after resection; well-differentiated forms metastasize late or not at all


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Leiomyoma/Leiomysarcoma (CIDP)

  • Leiomyoma

    • >95% of leiomyomas in female genital tract

    • in addition to female genital tract, leiomyosarcomas occur in the retroperitoneum, wall of the gastrointestinal tract, and subcutaneous tissue

    • benign - small, multiple, adolescence and early adulthood

  • Leiomyosarcoma

    • malignant – uncommon

    • superficial - good prognosis; deep - poor prognosis

    • Histologically, leiomysarcoma is differentiated from leiomyoma by the number of mitoses per high power field


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Rhadbomyosarcoma (CIDP)

  • Rhadbomyosarcoma

    • Children; one of more common soft tissue tumors in head/neck/urogenital areas; highly malignant

    • rapidly enlarging masses located near surface of body

    • deep neoplasms grow to large masses; 20-40% have metastases at diagnosis

    • SARCOMA BOTRYOIDES - variant of embryonal form; grapelike clusters, occurs in children under 10; nasopharynx, bladder, vagina

    • Stain with vimentin

  • Synovial Sarcoma

    • Multipotential mesenchymal cells, not synovial cells

    • develop in vicinity of large joints (knee); deep seated mass that has been noted for several years;

    • morphologically resembles synovium

    • t(X;18) translocation


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Vulva (CIDP)

Bartholin cyst - acute infection of Bartholin gland may lead to blocked duct with abscess; excise or permanently open duct

Vulvar vestibulitis - glands at posterior introitus can be inflamed; chronic, recurrent condition is very painful and can lead to small ulcerations; surgical removal of inflamed mucosa may help

Lichen simplex chronicus—aka hyperplastic dystrophy

Results from chronic rubbing/scratching secondary to pruritus

Can occur in eczema, psoriasis, nervousness, etc.

thickening of vulvar squamous epith. and hyperkeratosis

Not precancerous


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Vulva – Miscellaneous Disorders (CIDP)

  • Lichen sclerosus—aka chronic atrophic vulvitis

    • Thinning of epidermis, degeneration of basal cells, replacement of dermis with fibrous tissue and lymphocytic infiltrate

      • Lymphocytic cell infiltrate → underlying dermal fibrosis

    • Epidermis becomes thinned, scarred, and hyperkeratotic

      • Skin is pale gray and “parchment-like”

    • Labia is atrophied

    • Most common after menopause

    • not precancerous, but risk of subsequent carcinoma is 1-4%


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Vulva – Neoplasms of the Vulva (CIDP)

  • Papillary hidradenoma

    • Most common benign tumor of the vulva

    • Presents as a nodule at labia majora or interlabial folds with tendency to ulcerate and bleed

    • consists of tubular ducts with myoepithelial layer characteristic of sweat glands and sweat gland tumors

    • Cure is via simple excision

  • Condyloma acuminatum – benign sq. cell papilloma

    • Caused by HPV (usually types 6 and 11)

    • A proliferation of stratified squamous epithelium

    • Wartlike lesions, usually multiple and coalescing

      • koilocytotic atypia (nuclear atypia and perinuclear vacuolization)

      • in healthy individuals, it will regress


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Vulva - Cancer (CIDP)

  • Vulvar carcinoma—rare; 3% of all female genital ca; 85% squamous cell

    • Peak occurrence in older women

    • Preceded by pre-malignant changes

      • Vulvar intraepithelial neoplasia (VIN) 1-3, and/or vulvar dystrophy

    • Associated with high risk HPV (types 16, 18, 31, 33)

      • Same ones that cause sq. cell CA of the cervix and vagina

      • Other HPV types cause papillomatous lesions elsewhere

    • Associated with squamous cell hyperplasia and Lichen sclerosus


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Vulva - Cancer (CIDP)

  • Extramammary Paget Disease

    • Large tumor cells in epidermis of labia majora demarcated from normal epithelial cells

    • present with pruritic, red, crusting, sharply demarcated area

    • Cells show apocrine, eccrine and keratinocyte differentiation

    • Clear cells containing glycogen

    • Sometimes associated with underlying adenocarcinoma of the apocrine sweat glands


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Vagina (CIDP)

  • Atresia/total absence (extremely rare)

    • Deformed/non-functioning vagina, or total lack of vagina (vaginal agenesis)

    • Usually manifests at puberty due to amenses

    • Disruption of uterovaginal flow requires emergent surgery

  • Septate/double vagina

    • rare; failure of total fusion of mullerian ducts (longitudinal septum), or the failure of mullerian ducts to fuse with the urogenital sinus (transverse septum

      • Septum that runs either longitudinally or transverse

    • May be asymptomatic

      • A transverse septum is more likely to block uteran outflow and result in amenorrhea


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Vagina (CIDP)

  • Gartner duct cyst

    • Retention cyst arising from Gartner’s ducts occurring along the remnants of Wolffian ducts

    • Usually asymptomatic and small

  • Vaginal Intraepithelial neoplasia (VAIN) – CIN of the vagina

    • precancerous lesion; high riskpapilloma viruses (types 16, 18), may be multicentric

      • (analogous to high-grade CIN)

      • 10-30% associated with squamous neoplasm in vulva or cervix

    • graded as mild, moderate, or severe

    • white or pigmented plaques on the vagina

    • risk of progression to invasive cancer ↑ with age/immunosuppression


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Vagina (CIDP)

  • Squamous cell carcinoma

    • rare; (0.6/100,000 yearly)

    • 95% squamous cell, upper posterior vagina

    • Usually due to extension of sq. cell CA of the cerivx or vulva

      • #1 risk factor – sq. cell CA in cervix or vulva

      • Vagina usually not the primary site


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Vagina (CIDP)

  • Adenocarcinoma (clear cell variant)

    • Clear cell variant found in daughters of mothers who took diethylstilbestrol (DES), an anti-abortificant (only 0.14% develop it)

    • Presents age 15-20

    • Vaginal adenosis = precursor to clear cell adenocarcinoma

  • Embryonal rhabdomyosarcoma

    • <5 yo; tumor of malignant embryonal rhabdomyoblasts; bulky mass

    • may fill and project out of vagina (sarcoma botryoides)

      • Projection resembles a “bunch of grapes”


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Cervix (CIDP)

  • Endocervical polyps

    • Soft, mucoid polyps w/loose, fibromyomatous stroma

    • inflammatory proliferation of cervical mucosa – NOT TRUE NEOPLASMS

    • found in 2-5% of adult women

      • Most in endocervical canal; may protrude thru os

      • Protrustion can lead to irregular spotting and post-coital bleeding

    • associated with dilated mucous-secreting endocervical glands

    • inflammation, squamous metaplasia

    • Tx - simple curettage or surgical excision


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Cervix (CIDP)

  • Cervical Intraepithelial Neoplasm (CIN)

    • HPV most important agent (95% of cervical ca), but NOT only factor in development of

    • Viral gene product E6—interrupts cell death cycle by binding p53

    • E7—bind RB and disrupts cell cycle

    • CIN stages

      • CIN I – mild dysplasia involving lower 1/3 – raised or flat lesion, indistinguishable from condylomata accuminata

      • CIN II – moderate dysplasia – atypical cells in lower 2/3

      • CIN III – severe dysplasia/ carcinoma in situ (if it’s full thickness)

      • **Koilocytes may be present at all stages**

    • Takes 10 years to go CIN I→CIN II

    • Takes another 10 to go CIN II→CIN III


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Cervix (CIDP)

  • Squamous cell carcinoma – 95% of cervical cancer

    • Peak occurrence in middle aged women

    • Usually from pre-existing CIN at squamocolumnar jxn

    • PAP decreases mortality via early detection of CIN and CA

    • Intraepithelial and invasive neoplasm

    • 3 forms - fungating (exophytic), ulcerating, infiltrative

    • extends by direct continuity

    • metastasizes to lymph nodes; liver, lungs, bone marrow

    • PAP decreases mortality via early detection of CIN and CA

    • Histology - 95% large cells, keratinizing or non-keratinizing


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Cervix (CIDP)

  • Cinical Course/Management

    • Symptoms - irregular vaginal bleeding, leukorrhea, bleeding or pain on coitus; dysuria

    • PAP smear is insufficient for prevention/diagnosis

    • All abnormalities visualized by colposcopy

    • Acetic acid application will reveal CIN

      • White patches of cervix; follow up with punch biopsy

    • CIN I - Pap smear follow-up

    • CIN II, III – cryotherapy, laser, loop electrosurgical excision procedure (LEEP), or cone biopsy

    • Invasive CA - hysterectomy and/or radiation (depends on stage)

    • Survival: 80-90% stage I; 75% stage II; 35% stage III; 10-15% stage IV


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Uterus (CIDP)

  • Endometrial Hyperplasia

    • Abnormal proliferation of endometrial glands, usually caused by excess estrogen stimulation

    • Excess estrogen may be due to…

      • Anovulatory cycles, polycystic ovary dz, estrogen-secreting ovarian tumors (ex. granulosa cell tumors), and estrogen replacement therapy

    • Manifest clinically with postmenopausal bleeding

    • Can be a precursor lesion of endometrial carcinoma

      • Risk of CA directly correlated with degree of cellular atypia

    • Simple hyperplasia (aka cystic or mild) rarely leads to carcinoma

    • high grade (atypical or adenomatous + atypia) - cellular atypia, irregular epithelium; 25% lead to carcinoma


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Female Genital Uterus (CIDP)

  • Endometrial Carcinoma:

    • Most common invasive cancer of female genital tract and has best prognosis

    • Associated with prolonged estrogen stimulation, nulliparity, diabetes, obesity, hypertension, infertility

    • 55-65 year old women; present with bleeding

    • Most are well differentiated with a glandular pattern (85% adenocarcinoma), can be polyploid or diffuse

      • Less common variants: papillary serous- older women, more aggressive; tumors with squamous elements

    • Most forms spread by direct extension, metastasize late


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Female Genital Uterus (CIDP)

  • Endometrial Polyps:

    • benign sessile masses of any size

    • Asymptomatic or irregular bleeding

      • Most common cause of menorrhagia 20-40 age group

    • Two types- functional endometrium or cystic hyperplastic

    • association with endometrial hyperplasia and tamoxifen


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Female Genital Uterus (CIDP)

  • Hyperestrinism

    • Anovulatory cycles: excessive estrogen stimulation relative to progesterone

      • associated with polycystic ovarian syndrome, obesity, malnutrition, systemic disease

      • Common at menarche and perimenopausal

    • Inadequate luteal phase: deficient progesterone production by corpus luteum

      • Manifests as infertility, menorrhagia or amenorrhea

    • Iatrogenic: oral contraceptives, estrogen replacement


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Menstrual Cycle (CIDP)

  • Proliferative Phase: estrogen mediated

    • proliferation of glands and stroma

  • Ovulation: stimulated by LH surge

    • Confirmed by: basal vacuolization of epithelium, secretory or predecidual changes

  • Secretory Phase: progesterone mediated

    • Most prominent during 3rd week, tortuous glands and spiral arterioles, 4th week shows exhaustion and gland atrophy

  • Menstrual Phase : prostaglandin mediated

    • Prostaglandins  vasospasm and necrosis spasm of the myometrium

    • basal layer remains, upper 2/3 of endometrium shed


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Female Genital Uterus (CIDP)

  • Leiomyoma (fibroids)

    • Most common tumors in women

    • Reproductive age; blacks>whites

    • Estrogen sensitive

    • characteristic whorled pattern of smooth muscle bundles

    • Often asymptomatic; may cause bleeding, infertility

  • Leiomyosarcoma:

    • 40-60 year olds; not preceeded by leiomyoma; rare

    • characterized by cellular atypia and high mitotic index; >10 mitoses per high power field (400X

    • metastasis to lungs, bone, brain, and abdomen


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Fallopian Tubes (CIDP)

  • Inflammation: PID causes suppurative salpingitis, may result in hydrosalpinx; N. gonorrhoeae – 60% of cases, C. trachomatis also common

    • Complications: infertility, adhesions

  • Neoplasia:

    • paratubal cysts – Mullerian duct remnants form hydatids of Morgagni found in fimbria and ligaments; translucent and filled with serous fluid

    • Uncommon: adenomatoid, papillary adenocarcinoma


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Testicular Cancer (CIDP)

  • Sex Cord-Stromal Tumors (5%):

  • Leydig (Interstitial) cell tumor-

    • 20-60 years old, most benign, androgen producing

    • Presents as testicular swelling, gynecomastia or precocious puberty

    • Brown, homogenous, circumscribed nodules; Reinke crystals

  • Sertoli cell tumor (Androblastoma)-

    • Gray-white, homogenous, trabeculae resemble seminiferous tubules

    • Secrete androgens, but not clinically significant; benign


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Endometriosis (CIDP)

  • Presence of endometrial glands/stroma outside of the uterus

  • Found in ovaries, uterine ligaments, rectovaginal septum, pelvic peritoneum

  • Common cause of INFERTILITY

  • Dysmenorrhea, dyspareunia, dyschezia

  • Tissue under hormonal control = cyclic changes w/ bleeding during normal menstrual cycle

  • “chocolate cysts” in ovaries (blood, lipid debris); scarring of fallopian

  • Likely causes: Retrograde menstruation, Differentiation of dispersed coelemic epithelium, Lymphohematogeous spread


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Ectopic Pregnancy (CIDP)

  • Implantation of fetus in any site other than uterus

    • Tubes (90%), ovary, abdominal cavity, cornual end

  • 1/150 pregnancies

  • Predisposing factors – PID w/ chronic salpingitis (35-50%), peritubal adhesions from appendicitis or endometriosis, leiomyomas, previous surgery, IUD

  • Embryo undergoes usual development, but placenta is poorly attached, may separate and cause hematosalpinx or rupture

  • Presents most commonly with pain, pelvic hemorrage, shock, sx of acute abdomen – MEDICAL EMERGENCY!


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Polycystic Ovary Disease (CIDP)

previously known as Stein-Leventhal syndrome

*Numerous cystic follicles*

persistent anovulation, obesity, hirsutism, and rarely virilism

Ovaries(bilateral) 2x normal size and studded w/subcortical cysts; theca interna hyperplasia; Corpora Lutea ABSENT

LH stimulation of theca lutein cells excessive production of androgens which is converted to estrogens

Caused by unbalanced or asynchronous release of LH by pituitary:  LH,  FSH,  testosterone

Associated w/ Insulin resistance;  risk of endometrial cancer; prolactinoma may be involved in 25%


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Ovarian Epithelial Tumors (CIDP)

  • 65-70% overall frequency, 90% of malignant ovarian tumors

  • histology: cystadenomas, cystadenofibromas, adenofibromas

  • risk of malignancy increases with amount of solid epithelial growth

  • Clinical signs: low abdominal pain/enlargement, GI complaints, urinary complaints, ascites with peritoneal extension (exfoliated cells in fluid)

  • Metastasis to liver, lungs, GI, regional nodes, opposite ovary common

  • 80% of serous and endometrioid tumors positive for CA-125

  • BRCA is a marker for increased risk

  • fallopian tubal ligation and OCT reduce relative risk


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Ovarian Epithelial Tumors (CIDP)

  • Serous tumors

    • Tall, ciliated columnar epithelial lined serous fluid filled cysts, on surface of ovary

    • Can be benign or boarderline (age 20-50) or malignant (>50)

    • Serous cystadenocarcinomas are most common malignant ovarian tumor (40%)

    • Often bilateral and contain psammoma bodies

    • Benign: smooth cyst wall, no epithelial thickening

    • Boarderline: increasing papillary projections into cyst, some nuclear atypia, no destruction of stroma

    • Peritoneal spread with desmoplasia causing intestinal obstruction


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Ovarian Epithelial Tumors (CIDP)

  • Mucinous tumors

    • Rare before puberty or after menopause

    • Large number of big cysts filled with glycoproteins, not on surface, not bilateral, tall columnar epithelium without cilia

    • Associated with pseudomxoma peritonei: extensive mucionous ascites

  • Endometrioid tumors

    • Unlike mucinous and serous, most are endometrioid tumors are malignant

    • Contain tubular glands that resemble endometrium

    • Combination of cystic and solid areas, 50% bilateral

  • Clear Cell Adenocarcinoma

    • Large cells with clear cytoplasm


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Ovarian Epithelial Tumors (CIDP)

  • Cystadenofibroma

    • Pronounced desmoplasia underlying columnar ephithelial neoplasia

    • Metastatic spread is uncommon

  • Brenner tumors

    • Uncommon transitional cell tumors, sometimes found with mucinous cystadenomas

    • Usually unilateral, can become quite massive

    • Sometimes surrounded by plump fibroblasts with hormonal activity

    • Can secrete estrogens


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Stromal Ovarian Tumors (CIDP)***(all are unilateral)

Ganulosa-Thecal (mixed: gran=malignant, thecal=benign)

Sheet/cords of cuboidal to polygonal cells

Call-Exner bodies: small follicles w/eosinophilic secretions

Estrogen secreting: precocious puberty

Assoc. w/endometrial hyperplasia/carcinoma (adult women)

Thecoma-Fibroma (benign)

Solid, bundles of spindle shaped fibroblasts w/lipid droplets

Meig’s Syndrome: R-sided hydrothorax, ovarian tumor, ascites

Hormonally inactive

Assoc. w/ basal cell nevus syndrome


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Stromal Ovarian Tumors (CIDP)***(all are unilateral)

Sertoli-Leydig:

Golden-brown on cross section

Cords of Sertoli or Leydig cells

Androgen/estrogen production = virilization

May contain mucinous glands, bone, cartilage

Hilus Cell Tumors: rare

benign, pure Leydig

↑ 17-ketosteroid unresponsive to cortisone suppression

Gonadoblastoma: rare

persons w/abnormal sexual development

Coexisting dysgerminoma

Pregnancy Luteoma: rare

assoc w/corpus luteum

virilization of mother and child


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Teratomas (CIDP)

  • Germ cell tumor with all three germ layers

  • From totipotent cells  usually found in gonads

  • 3 categories:

    • Mature (benign) – most are cystic (dermoid cysts), tissue resembles adult tissue, unilateral, karyotype 46,XX, reproductive females

    • Immature (malignant) – rare, tissue resembles fetal or embryonic tissue, adolescent women

      • Frequently metastasize through capsule

    • Monodermal (specialized) – rare, unilateral, may be functional

      • struma ovarii – thyroid tissue, can cause hyperthyroid

      • ovarian carcinoid – from intestinal epithelium, produces 5-HT


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Non-Neoplastic Breast Disease (CIDP)

FIBROCYSTIC CHANGE:

  • Most common breast condition

  • bilateral/multiple formation of blue-domed cysts that result in pain/tenderness that varies cyclically

  • causes microcalcification (confused with cancer)

    GYNECOMASTIA: most commonly caused by cirrhosis; usually unilateral

    PROLIFERATIVE DISEASE: proliferation of epithelial/glandular tissue; increased risk for carcinoma if >4 epithelial layers or atypia;

    Sclerosing Adenosis: increased numbers of acini compressed by fibrous tissue (slit-like); slight increase in cancer


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Inflammatory Breast Disease (CIDP)

  • Fat necrosis: trauma-related; chalky, white, hard lesions from saponification

  • Lactation Mastitis: staph infection from nursing; may abscess

  • Galactocele: cystic dilation with viscous “milk” after lactation cessation

  • Mammary Duct Ectasia: interstitial granulomatous inflammation leading to duct dilation; thick/sticky nipple discharge, lump/retracted nipple; post-menopause

  • Periductal Mastitis: keratinizing squamous metaplasia leading to duct ingrowth and abscess/fistula formation; associated with SMOKING

  • Granulomatous Mastitis: epithelial granulomas in multiparous women; may be a hypersensitivity reaction secondary to lactation

  • Silicone Breast Implants:  chronic inflammation/fibrosis


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Ductal Breast Carcinoma (CIDP)

  • Typically divided into Ductal Carcinoma in Situ (DCIS) and Invasive Ductal Carcinoma

  • DCIS: periductal concentric fibrosis with chronic inflammation

    • Linear or branching microcalfications seen on mammography; associated with intraductal necrosis

  • Invasive: streaks of white elastic stroma with foci of calcification, irregular borders signifying escape from the ductal basement membrane; highly scirrhous, desmoplastic tumor

  • If mass is palpable, half of patients will have lymph node metastasis

  • Fixation to chest wall, lymphedema  peau d’orange, cooper ligament tethering to skin, retraction of nipple


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Non-ductal breast carcinoma (CIDP)

  • Lobular carcinoma in-situ

    • Proliferation in one or more terminal ducts – distended lobules

    • Incidental finding on biopsy for another reason – nonpalpable

    • Often multifocal and bilateral, can progress to carcinoma

    • No cell adhesion – lack e-cadherin

  • Invasive lobular carcinoma

    • Tends to be bilateral and muliticentric

    • Single file cells, can be concentric and have bull’s eye appearance

    • Present as palpable mass or density on mammogram

    • Well differentiated tumors express hormone receptors


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Non-ductal breast carcinoma (CIDP)

  • Medullary carcinoma

    • Associated with BRCA-1 mutation

    • Bulky, soft tumor with large cells and lymphocytic infiltrate

  • Colloid carcinoma

    • Occurs in older women, grows very slowly

    • Cells surrounded by extracellular pale gray-blue mucin

  • Tubular Carcinoma

    • Women in late 40’s

    • Well-formed tubules in terminal ductules

    • Absence of myoepithelial layer

    • Multifocal or bilateral tumors


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Spontaneous abortions (CIDP)

  • 10-15% of recognized pregnancies; probably close to 22% of all conceptions; chromosomal studies are recommended with habitual or recurrent abortion or with malformed fetus

  • fetal influences

    • defective implantation

    • genetic or acquired developmental abnormality

    • chromosomal abnormalities in >50%

  • maternal influences

    • inflammatory diseases (local and systemic),

    • uterine abnormalities

    • infection


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Placenta (CIDP)

  • Placental abnormalities

    • placenta acretia - partial or complete absence of the decidua with adherence of placenta directly to myometrium; failure of placental separation may cause postpartum bleeding (life threatening); up to 60% association with placenta previa; uterine rupture (placenta percreta)

    • placenta previa - implantation in the lower uterine segment or cervix associated with serous antepartum bleeding and premature labor

    • placenta abruptio – separation of the placenta prior to delivery

  • Twin placenta

    • monochorionic implies monozygotic twins; may have one or two amnions

    • dizygotic twins usually have dichorionic, diamniotic placenta


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Pre-eclampsia/eclampsia (CIDP)

  • Pre-Eclampsia: hypertension, proteinureia, and edema

  • Eclampsia: add convulsions, CNS disturbances, and DIC

  • 6% of pregnant women; last trimester; primiparas

  • DIC in eclampsia results in lesions in liver, kidneys, heart, placenta, and brain

  • The primary pathology appears to involve inadequate placental blood flow and ischemia; trophoblast-dependent

  • HELLP syndrome - hemolysis/elevated liver enzymes/low platelets associated with microangiopathic hemolysis with DIC and fibrin deposition

  • Eclampsia is heralded by convulsions. It usually represents vascular damage to the CNS with the development of DIC.

    • Microscopic lesions include arteriolar thrombosis, arteriolar fibrinoid necrosis, petechial hemorrhages, and diffuse microinfarcts.


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Complete (Classic) Mole (CIDP)

  • characterized by growth and cystic swelling of COMPLETE chorionic villi with trophoblastic proliferation

  • NO EMBRYO IS PRSENT; uterus is filled with grape-like clusters; volume is MUCH GREATER than in normal pregnancy

  • more than 90% have 46,XX diploid pattern, all derived from the sperm (duplication of uniploid sperm; 46YY not viable)

  • proliferation of both cytotrophoblasts and syncytiotrophoblasts

    • grape-like clusters of swollen, watery chorionic villi

    • villi are not atypical in structure

  • presents about 14th week (8-24 wk) with vaginal bleeding, uterus larger than normal pregnancy, high HCG levels

  • about 10% develop persistent trophoblastic disease and 3-5% WILL DEVELOP CHORIOCARCIOMA


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Other Moles (CIDP)

  • Incomplete (Partial) Mole

    • Villi INCOMPLETELY involved; usually focal

    • karyotype is triploid (69,XXY) or tetraploid (92,XXXY)

    • EMBRYO IS VIABLE for weeks, so fetal parts may be found

    • Presentation with nonviable fetus and irregular vaginal spotting, but uterine size NOT increased and NO increased risk of choriocarcinoma

  • Invasive mole

    • mole that penetrates and may even perforate uterine wall; tumor is locally destructive

    • vaginal bleeding and irregular uterine enlargement; persistent elevated HCG; may present several weeks after a mole has been evacuated

    • hydropic villi may embolize to lungs and brain, but do not grow as true metastases; responsive to chemotherapy


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Choriocarcinoma (CIDP)

  • epithelial malignancy of trophoblastic cells from previously normal or abnormal pregnancy

  • rapidly invasive, widely metastasizing; but responds well to chemotherapy

  • 50% arise in hydatidiform (classic) moles (1 in 40 moles), 30% in previous abortions, 22% in normal pregnancies

  • no chorionic villi; proliferation of both cytotrophoblasts surrounded by rim of syncytiotrophoblasts

  • does not produce large, bulky mass

  • produces high levels of HCG in absence of pregnancy

  • metastases to lungs, vagina, brain, liver, kidney